|Respiratory sequelae of viral diseases: from diagnosis to treatment
Seqüelas respiratórias de doenças virais: do diagnóstico ao tratamento
|Alejandro TeperGilberto Bueno FischerMarcus Herbert Jones|
J Pediatr (Rio J) 2002;78(Suppl.2):s187-s94
Objective: the objective of the present article is to present
a review of the main clinical issues faced by pediatricians while defining
the diagnosis, management and prognosis of postinfectious bronchiolitis
The advances in intensive therapy that have occurred over the last few years have allowed the survival of many children who, after being affected by serious respiratory infections, develop persistent and severe ventilatory sequelae. This clinical syndrome is called postinfectious bronchiolitis obliterans (BO)(). Its main characteristics are the severity of respiratory obstruction, the absence of response to the treatments employed as opposed to the most benign and self-limited conditions that follow acute viral bronchiolitis. The patient typically has wheezing, tachypnea, dyspnea, and persistent cough for weeks or months after the initial infection. The disease may persist for years after its onset and may worsen due to exacerbations caused by viral infections, causing suppuration, atelectasis, and pneumonias( ). There are no epidemiological data available, but apparently BO has a high prevalence in the southern region of Brazil, in Uruguay, Argentina and Chile, and it is one of the main causes of chronic obstructive pulmonary diseases in children in these regions, generating a demand for hospital and clinic services similar to that observed in patients with cystic fibrosis. The knowledge about the risk factors, physiopathology, inflammatory and pulmonary function disorders caused by this disease, which is not so rare in our patient population, is still scarce.
Bronchiolitis obliterans is a disease characterized
by an inflammatory process and fibrosis of the airways. Among the several
etiologies described in children, such as inhalation of toxic substances,
aspiration syndromes, and immunological diseases, postinfectious BO is
the most frequent cause in our patient population. The major infectious
agents that trigger fibrosis are the influenza, parainfluenza, and measles
viruses, adenovirus, and respiratory syncytial virus(
Adenovirus is associated with the most severe
cases. Factors such as viral genotype, immune response, viral load, genetic
The typical histological pattern of postinfectious
BO is that of constrictive bronchiolitis, characterized by variable obstruction
of the airways by fibrous tissue. In general, it is a lesion of the small
airways with slight involvement of the pulmonary parenchyma. The bronchial
mucous membrane is affected and its lumen is occupied by fibrous tissue,
producing partial or total obstruction of terminal bronchioli. Collagen
deposition occurs on the submucosa, leading to the progressive concentric
narrowing and distortion of the bronchial lumen, mucus stasis and chronic
Functional studies involving children and infants have revealed, almost invariably, an enhanced reduction of expiratory flows. Bronchiolitis obliterans with a constrictive pattern is usually characterized by fixed obstruction and minimum response to the administration of corticoids(). Table 1 presents the main pulmonary functional studies in children with BO. The obstructive pattern is predominant, especially when the test is applied in the first months or years after the initial event, as shown by Teper( ) and Jones( ). Forced expiratory maneuvers show remarkable concavity and reduction of expiratory flows, especially of tele-expiratory flows. Figure 1 presents a forced expiratory maneuver performed in a 19-month-old infant with BO. The presence of reduced vital capacity suggesting a restrictive pattern occurs in few patients and is probably secondary to air entrapment. In the studies in which pulmonary volume was measured, the vast majority of patients presented a normal total pulmonary capacity ( ). The functional studies performed several years after the onset of the disease showed an improvement in the ventilatory obstruction and normal spirometry in some patients( ).
Table 1 -
Figure 1 - Flow-volume
curve obtained from a 19-month-old infant with postinfectious bronchiolitis
obliterans. A severe obstructive pulmonary disease, presenting abrupt
concavity of the forced expiratory curve with extremely reduced flows.
Vital capacity within normal limits.
The diagnosis of BO is based on the past history of a lower airway infection,
usually an acute viral bronchiolitis followed by a persistent chronic
obstructive pulmonary disease. Clinically, the disease is characterized
by cough, wheezing, crepitations and hypoxemia, which persist beyond the
normal period observed in a bronchiolitis. Older children present intolerance
of physical exercise and, quite often, tapering fingers. Initially, what
draws our attention to this disease is the persistence of obstructive
symptoms and the absence of response to the employed treatments, even
with the use of systemic corticoid in high doses and the continuous use
of oral and/or inhaled bronchodilators().
A plain chest x-ray typically reveals pulmonary hyperinflation, thickening
of the bronchovascular bundles, hyperlucency, bronchiectasis, and atelectasis(. )
Bronchography, used until recently as a method for the detection of bronchiectasis,
is no longer used since it is too invasive and due to the availability
of higher quality methods such as computed tomography (CT). Nowadays,
the exam that best describes pulmonary disorders is high-resolution CT(.
In Zhang )(
series, the following disorders were observed, in order of frequency:
bronchial thickening, bronchiectasis, and a mosaic pattern, which corresponds
to areas of higher and lower attenuation (Figure 2). A CT is more sensitive
than a conventional radiogram for the detection of segmental and subsegmental
atelectasis and bronchiectasis. In addition, the comparison of inspiratory
and expiratory images offers the possibility of combining structural and
functional information, thus enabling the assessment of the presence of
air entrapment and hypoxic vasoconstriction( ).
The method is limited by the need for intubation and anesthesia in young
children and the exposure to radiation exceeding over 100 times the radiation
of a plain chest x-ray. Recently, some authors have proposed the use of
a laryngeal mask or simply positive airway pressure instead of anesthesia
and tracheal intubation to perform a CT examination, which may potentially
increase the safety of the exam )(.
However, the indication of high-resolution CT for the investigation of
BO should be limited to patients in whom the disease is highly suspected.
Figure 2 -
The final diagnosis is obtained by means of an open lung biopsy. However,
according to several authors, diagnosis can be done with a large margin
of safety, based upon the presence of persistent symptoms of obstructive
pulmonary disease and specific alterations on chest computed tomography(.
Recent studies, which combine high-resolution CT and lung biopsy have
confirmed this )(.
It is important to emphasize that lung biopsy not always confirms the
diagnosis. According to the heterogeneous distribution of pulmonary lesions,
the material obtained from a lung biopsy may contain slight histopathological
alterations, which might easily go unnoticed )(.
The proposed diagnosis of postinfectious BO is based on the following criteria:
1) initial infectious event;
2) persistence of obstructive symptoms, such as wheezing, crepitations, dyspnea for over 6 weeks after the initial event;
3) high-resolution computed tomography showing bronchiectasis and a mosaic pattern;
4) exclusion of pulmonary disorders, such as cystic fibrosis, foreign
body aspiration, congenital malformation, tuberculosis, AIDS, and other
The treatment of bronchiolitis obliterans
has not been universally established yet. Most pediatric pneumology services
use a combination of corticoids and bronchodilators continuously, in addition
to other supportive measures.
Apparently, the disease, once established,
has characteristics of fixed obstruction. However, a variable obstructive
component may also be present. This component is characterized by periods
of recovery and worsening, possibly due to the sporadic response to the
bronchodilator; which might also be an expression of bronchial hyperreactivity.
As the characteristics of the pulmonary inflammatory process (especially
its duration) are unknown, the use of corticoids is maintained for long
periods of time, not with the intention of reversing the fixed and severe
obstruction, but with the aim of reducing bronchial hyperreactivity and
bronchoconstriction secondary to viral infections and allergy.
Similar studies have not yet been performed
in humans. There have not been enough studies in order to affirm that
corticosteroids might play a decisive role in the control of the original
inflammatory process or in the prevention of the progression of postinfectious
BO in children. Their use is based on successful reports on adult BO patients
The form of dispensing corticoids is controversial.
Pulse therapy (IV methylprednisolone, 30mg/kg/day
for three days) every 30 days has been proposed to reduce the side effects
of prolonged systemic administration of corticoids, and has been an alternative
for patients with severe BO. Limited and non-controlled reports on pulse
therapy have proved successful(
Just like oral or inhaled corticosteroids,
bronchodilators (BD) are also empirically indicated. Their use can partially
reduce the obstructive symptoms, especially in the first two years of
life. Inhaled short-acting ß2-adrenergics, dispensed in metered
dose aerosols with age-appropriate spacers, are preferable. The functional
evaluation before and after the use of BD in infants and children with
BO shows a variable response to the use of bronchodilators, but in most
patients an immediate response is not observed(
As far as long-acting ß2-adrenergics
are concerned, the therapeutic principles for severe persistent asthma
should be applied. In other words, these drugs should be used with the
intention of reducing the dose of inhaled or systemic corticoids and never
as a monotherapy. Nevertheless, there have been no studies so far that
precisely define the systematic use of these drugs.
Since many patients present frequent respiratory
infections and bronchiectasis, the use of antibiotics is often necessary.
Usually the bacteria isolated in these patients are the ones most commonly
found in the respiratory tract, such as Streptococcus pneumoniae, Haemophilus
influenzae, Brahmanella catharralis. Therefore, antibiotic therapy should
be focused on these causative agents. Bacterioscopy and sputum culture
may guide antibiotic therapy in older children. In younger children, information
on the etiology of infection may be obtained by tracheal aspiration or
by bronchoalveolar lavage. Such findings, however, should be carefully
assessed because it is often impossible to differ between colonization
and infection. In patients with diffuse bronchiectasis, the need for antibiotic
therapy is more frequent. The literature does not include any studies
that support the continuous use of antibiotics for this kind of patient.
A strategy is to use them in case of fever or when secretion worsens (increased
volume or thicker sputum). The length of use may vary from 14 to 21 days
in each course of antibiotics.
For children with BO, the main indications
for physical therapy are related to the treatment of bronchiectasis and
atelectasis. Just like in other therapeutic strategies for such patients,
the use of physical therapy is empirical, although its results can be
observed, with improvement of secretion retention, quality and quantity
of secretions, as well as re-expansion of atelectasis. Techniques for
the rehabilitation of ventilatory muscles may also be used in patients
with chronic and acute ventilatory obstruction. Its use in children has
not been widely studied, but inferences can be made based on studies involving
adults with chronic obstructive pulmonary disease.
Many patients need supplementary oxygen for
long periods (months or years) and some of them need it on a permanent
basis. Generally, the O2 concentrations necessary to maintain a saturation
above 94% are low (FiO2 from 0.25 to 0.4) and can be obtained through
portable oxygen concentrators((,
home oxygen therapy was informally implemented by means of donations and
support from the local community and from the medical staff. Later on,
a specific program for children who depended on oxygen was established
and maintained by the Unified Health System. )
Similarly to other chronic lung diseases
in which energy consumption is elevated, the patient should receive an
adequate calorie and energy supply. Even though such needs should be analyzed
on a case-by-case basis, the goal is to maintain the child's weight and
height adequate for his or her age. In cases in which it is not possible
to supply proteins and calories orally, the use of a nasogastric or nasoenteral
tube might be necessary for supplementary feeding. Also, in cases of patients
who cannot have an adequate supply of proteins and calories, a gastrostomy
should be performed.
In patients with localized bronchiectasis
or chronic lobar collapse, the resection of the affected lobe may avoid
a higher frequency of infectious exacerbations and reduce the need for
A surgical procedure to reduce pulmonary volume in cases of extreme pulmonary
hyperinflation has been proposed and the results have been encouraging( ).
A high frequency of gastroesophageal reflux
(GER) has been observed in children with BO(.
The reflux is probably caused by the increase of abdominal pressure due
to pulmonary hyperinflation, which is characteristic in such patients.
The diagnosis should be preferably made by 24-hour pHmetry. If this is
not possible, and whenever there is clinical suspicion, therapeutic measures
should be implemented, such as thickened foods, adequate positioning (the
supine position should be avoided), use of acid secretion inhibitors and
medication to accelerate gastric emptying. )
As in other chronic pulmonary diseases, environmental
preventive measures may have a considerable impact. Exposure to tobacco
must be avoided, as well as the contact with viral respiratory diseases,
especially in the first months after the initial viral infection. Great
attention should be paid to the possibility of nosocomial viral infection,
because these children have a higher risk of clinical deterioration if
exposed to new involvement of the respiratory tract. For the same reason,
the contact of these patients with other potentially infected children
in daycare centers and schools should be restricted, especially during
winter until the disease has stabilized.
Immunizations should be applied according
to the vaccine calendar. Vaccines for the prevention of respiratory diseases
such as those caused by Haemophilus influenzae type b, pneumococci and
the influenza virus may play an important role in reducing infectious
Transplantation should be considered for
patients who show a persistent and severe obstructive condition with decrease
in pulmonary function and growing needs for supplementary oxygen. In the
USA, three patients have been followed up for one to six years after lung
The possibility of lung transplant from a living donor from the patient's
family may be a good alternative for patients with end-stage disease )(.
In Porto Alegre, three patients with BO have undergone this kind of lung
Bronchiolitis obliterans has a variable course
depending on the level of the initial infection. Some patients have an
unfavorable outcome, with accelerated loss of pulmonary function, hypoxemia,
and CO2 retention, which leads to pulmonary hypertension and cor pulmonale.
Most patients with postinfectious BO present mild to moderate scenarios,
which results in a usually good prognosis, with low mortality. With supportive
treatment and adequate medical follow-up the patient's quality of life
and pulmonary function are gradually improved and the need for supplementary
oxygen is reduced().
Postinfectious BO is not a very well known
clinical entity, especially with regard to its prevention and prognosis.
Since it is a disease that has affected a significant number of infants
in Latin America, it is necessary to carry out cooperative studies in
order to identify the risk factors of this disease and other aspects that
may result in a better treatment. A group of Latin American pediatricians
and pediatric pneumologists have been carrying out research about BO,
which may help to understand the physiopathology and treatment of this
Every child who has a chronic obstructive disease needs an appropriate investigation, which should be made in reference centers that have the necessary resources for a specific and differential diagnosis of this condition. These patients should proceed with continuous pediatric follow-up since the pediatrician is the one who should be in charge of the supportive measures. As soon as the diagnosis has been established, the pediatrician has to focus on the individual needs of patients with chronic diseases as to their nutrition, immunizations, evaluations and treatment of infectious exacerbations, emotional support, identification of learning difficulties, among several others.
|Alejandro Teper - Pediatric Pulmonologist, Hospital de Ninos Ricardo Gutierrez.|
|Gilberto Bueno Fischer - Professor, Fundação Faculdade Federal de Ciências Médicas de Porto Alegre.|
|Marcus Herbert Jones - Professor, Department of Pediatrics, Pontifícia Universidade Católica do Rio Grande do Sul.|
|Top | Close|
|Title of the article: "Respiratory sequelae of viral diseases: from diagnosis to treatment"|
|1. Lynch DA, Brasch RC, Hardy KA, Webb WR. Pediatric pulmonary disease: assessment with high-resolution ultrafast CT. Radiology 1990;176(1):243-8.|
|2. Hardy KA, Schidlow DV, Zaeri N. Obliterative bronchiolitis in children. Chest 1988;93(3):460-6.|
|3. Zhang L, Irion K, Kozakewich H, Reid L, Camargo JJ, da Silva Porto N, et al. Clinical course of postinfectious bronchiolitis obliterans. Pediatr Pulmonol 2000;29(5):341-50|
|4. Hardy KA. Obliterative Bronchiolitis. In: Hilman BC, editor. Pediatric Respiratory Disease: diagnosis and treatment. Philadelphia: Saunders; 1993. p. 218-21.|
|5. Fischer GB, Mocelin HT. Bronquiolite Obliterante - Seqüelas de Bronquiolite. In: Rozov T, editor. Doenças Pulmonares em Pediatria. Diagnóstico e Tratamento. São Paulo: Atheneu; 1999. p. 199-204.|
|6. Ferkol TW, Davis PB. Bronchiectasis and Bronchiolitis Obliterans. In: Taussig L, editor. Pediatric Respiratory Medicine. Saint Louis: Mosby; 1999. p. 784-92.|
|7. Chan PW, Muridan R, Debruyne JA. Bronchiolitis obliterans in children: clinical profile and diagnosis. Respirology 2000;5(4):369-75.|
|8. Sly PD, Soto-Quiros ME, Landau LI, Hudson I, Newton-John H. Factors predisposing to abnormal pulmonary function after adenovirus type 7 pneumonia. Arch Dis Child 1984;59(10):935-9.|
|9. Wenman WM, Pagtakhan RD, Reed MH, Chernick V, Albritton W. Adenovirus bronchiolitis in Manitoba: epidemiologic, clinical, and radiologic features. Chest 1982;81(5):605-9.|
|10. Kajon AE, Larranaga C, Suarez M, Wadell G, Avendano LF. Genome type analysis of Chilean adenovirus strains isolated in a children's hospital between 1988 and 1990. J Med Virol 1994;42(1):16-21.|
|11. Macek V, Sorli J, Kopriva S, Marin J. Persistent adenoviral infection and chronic airway obstruction in children. Am J Respir Crit Care Med 1994;150(1):7-10.|
|12. Kajon AE, Mistchenko AS, Videla C, Hortal M, Wadell G, Avendano LF. Molecular epidemiology of adenovirus acute lower respiratory infections of children in the south cone of South America (1991-1994). J Med Virol 1996;48(2):151-6.|
|13. Larranaga C, Kajon A, Villagra E, Avendano LF. Adenovirus surveillance on children hospitalized for acute lower respiratory infections in Chile (1988-1996). J Med Virol 2000;60(3):342-6.|
|14. Colby TV. Bronchiolitis. Pathologic considerations. Am J Clin Pathol 1998;109(1):101-9.|
|15. Mauad T, Dolhnikoff M. Histology of childhood bronchiolitis obliterans. Pediatr Pulmonol 2002;33(6):466-74.|
|16. Myers JL, Colby TV. Pathologic manifestations of bronchiolitis, constrictive bronchiolitis, cryptogenic organizing pneumonia, and diffuse panbronchiolitis. Clin Chest Med 1993;14(4):611-22.|
|17. Teper AM, Kofman CD, Maffey AF, Vidaurreta SM. Lung function in infants with chronic pulmonary disease after severe adenoviral illness. J Pediatr 1999;134(6):730-3.|
|18. Jones MH, Delfim ML, Kallfelz ML, Vitola L, Pitrez PMC, Stein R. Pulmonary Function In Infants With Post-Infectious Bronchiolitis Obliterans. In: ATS International Conference 2002; 2002; Atlanta, USA; 2002. p. A673.|
|19. Colom AJ, Maffey AF, Navarra F, Teper A. Pulmonary Function In Children With Post-Viral Chronic Pulmonary Disease (PCPD). In: ATS International Conference 2002; 2002; Atlanta; 2002. p. A159.|
|20. Kim CK, Kim SW, Kim JS, Koh YY, Cohen AH, Deterding RR, et al. Bronchiolitis obliterans in the 1990s in Korea and the United States. Chest 2001;120(4):1101-6.|
|21. Chang AB, Masel JP, Masters B. Post-infectious bronchiolitis obliterans: clinical, radiological and pulmonary function sequelae. Pediatr Radiol 1998;28(1):23-9.|
|22. Zhang L, Irion K, da Silva Porto N, Abreu e Silva F. High-resolution computed tomography in pediatric patients with postinfectious bronchiolitis obliterans. J Thorac Imaging 1999;14(2):85-9.|
|23. Long FR, Castile RG, Brody AS, Hogan MJ, Flucke RL, Filbrun DA, et al. Lungs in infants and young children: improved thin-section CT with a noninvasive controlled-ventilation technique--initial experience. Radiology 1999;212(2):588-93.|
|24.Schlesinger C, Meyer CA, Veeraraghavan S, Koss MN. Constrictive (obliterative) bronchiolitis: diagnosis, etiology, and a critical review of the literature. Ann Diagn Pathol 1998;2(5):321-34.|
|25. Moran TJ, Hellstrom
NR. Bronchiolitis Obliterans. An experimental study of the pathogenesis
and the use of cortisone in modification of the lesions. Arch Pathol 1958;66:691-707.
|26. Epler GR, Colby TV, McLoud TC, Carrington CB, Gaensler EA. Bronchiolitis obliterans organizing pneumonia. N Engl J Med 1985;312(3):152-8.|
|27. Mocelin HT, Fischer GB, Ranzi LT, Rosa RD, Philomena MR. Oxigenioterapia domiciliar em crianças: relato de sete anos de experiência. J Pneumol 2001;27:148-52.|
|28. Mocelin HT, Fischer GB, Ranzi LT, Wenzel G, Moraes RI. Surgery for bronchiectasis in children. In: ERS 2000 Annual Congress; 2000; Florence, Italy; 2000. p. 124s.|
|29. Bloch KE, Weder W, Boehler A, Zalunardo MP, Russi EW. Successful Lung Volume Reduction Surgery in a Child With Severe Airflow Obstruction and Hyperinflation due to Constrictive Bronchiolitis*. Chest 2002;122(2):747-50.|
|30. Meyer R, Fischer GB. Associação entre refluxo gastroesofágico e quedas da saturação transcutânea de oxigênio da hemoglobina em lactentes com doença ventilatória obstrutiva crônica. J Pediatr (Rio J) 2001;77(2):89-95.|
|31. Camargo JJ. Transplante de órgãos na infância: uma quimera? J Pediatr (Rio J) 2000;76(3):177-8.|
|32. Camargo JJ. Comunicação pessoal. In. Porto Alegre; 2002.|
|33. Kim MR, Lee HR, Lee GM. Epidemiology of acute viral respiratory tract infections in Korean children. J Infect 2000;41(2):152-8.|
|Top | Close|
| Copyright Sociedade Brasileira de Pediatria © 2001 - All rights reserved
All services in this site are free. This is possible thanks to a donation given by Nestlé Infants Nutrition